This invention embodies a new and novel process for the preparation of encainide (I) ##STR1## Encainide, chemically, 4-methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide, is a member of a series of antiarrhythmic 2-phenethylpiperidines bearing amide substituents in the ortho-position of the phenyl ring. Encainide hydrochloride is also referred to in the literature as MJ 9067-1 (USAN and the USP Dictionary of Drug Names, 1980, p. 122, United States Pharmacopeal Convention, Inc., 12601 Twinbrook Parkway Rockville, MD. 20852, Library of Congress Catalog Card No. 72-88571). Encainide is an FDA-approved drug for the treatment of certain cardiac arrhythmias.
Previous syntheses of encainide and closely related compounds are described in the following references.
Dykstra. S. J., et al., J. Med. Chem., 16, 1015-1020, (1973).
S. J. Dykstra and J. L. Minielli, U.S. Pat. No. 3,931,195 patented Jan. 6, 1967; U.S. Pat. No. 4,000,143 patented Dec. 28, 1978; U.S. Pat. No. 4,064,254 patented Dec 20, 1977.
Byrne J. E. et al., J. Pharmacology and Experimental Therapeutics, 200, 147-154 (1977).
Another process, different from syntheses disclosed in the above-cited references, is described in U.S. Pat. No. 4,394 507, which issued July 19, 1983.
The instant process differs from these previously disclosed processes and offers advantages that will be evident from the description of the invention.
The following references relate to condensation of aromatic aldehydes with quaternized .alpha.-picolinium halides.
a. Horwitz Journal of Organic Chemistry, 21, 1039-1041 (1956). PA1 b. Stanek, et al., Chem. Abstracts, 49, 314h (1955). PA1 c. Phillips, Journal of Organic Chemistry, 12, 333-341 (1947).
The condensation process disclosed and discussed in the above references a-c does not proceed readily with o-nitrobenzaldehyde, affording yields of only 40% or less of condensation product.
There is nothing in any of the above references or any other prior art that would suggest or make obvious the novel process embodied in the present invention.